Recurrent Aphthous Stomatitis (RAS) is a very common ulcerative oral mucosal disease of unknown etiology. The lack of understanding of the exact etiology and mechanism of ulcer formation in patients afflicted by this very painful condition has hampered the development of effective therapies. In order to plan and implement successful clinical trials leading to the development of better drugs for our patients we must first identify the cause of this disease. Most scientists agree that the immune system is activated in RAS. However, there is no agreement as to what leads to its activation and ultimately to the development of RAS. Modern medicine has identified intense cross-talks between the endocrine and immune system. In particular, growth factors, such as IGF-1 and leptin, have been shown to regulate the immune system and also wound healing. In two separate published population studies we have found a striking overlap in the distributions with age in RAS prevalence and these growth factors. These data, however, do not directly associate RAS and serum levels of growth factors within a single sample population. Our overall hypothesis is that an up-regulation of the IGF-1/leptin pathway is the primary source of immune activation and impaired wound healing in RAS patients. We propose a detailed person-level study of these factors through secondary statistical analyses of nationally representative data. Specific Aim 1 is to compare serum IGF-1 levels in individuals with and without RAS upon examination. Specific Aim 2 is to compare serum leptin levels in individuals with and without RAS upon examination. We expect higher IGF-1 and leptin levels in patients with active RAS vs. controls. These results will provide the first evidence that the levels of these growth factors are closely associated with the presence of painful ulcers. The results of these analyses will create the foundation for R01-level clinical research studies focused on the IGF-1/leptin pathway as the primary driving force leading to RAS formation. PUBLIC HEALTH RELEVANCE: Recurrent Aphthous Stomatitis (RAS;also known as canker sores) is a very common and painful disease of unknown cause that occurs primarily during growth. We have noted a remarkable overlap between RAS and certain growth factors that regulate wound healing, suggesting that this could be the pathway through which RAS develops. The identification of the specific mechanism that leads to RAS formation would open the door to the development of more targeted drugs, expected to have fewer side effects and greater efficacy, for patients suffering from this condition.